Bladder cancer is the 4th most common cause of cancer in men both in Europe and USA Three-quarters of tumors are diagnosed as non muscle-invasive (NMIBC) and remain confined to the bladder mucosa. According to specific tumor stage and grade characteristics, intravesical (ives) immunotherapy with Bacillus Calmette-Guerin (BCG) partially limit the high propensity of these tumors to recur and possibly progress after transurethral endoscopic resection. BCG reduces recurrence and progression of bladder cancer. However, side effects linked to either the ability of BCG bacteria to infect bladder tissues and possibly disseminate or the strong inflammation induced are encountered in close to 90% of the patients, ranging from cystitis to sepsis and death.
The precise mechanism of action of BCG remains unknown. However it was shown that after ives instillation BCG infects and is internalized by the urothelial and cancer cells and elicits a huge influx of inflammatory cells and cytokines that leads to an anti-tumor response (reviewed in (Askeland, Newton, O'Donnell, & Luo, 2012). Some strategies like combining cytokines with BCG, reducing doses of BCG, using mycobacterial cell wall to replace BCG, or using toll-like receptor (TLR) agonist to stimulate the immune system were tested in clinical trials or animal models (reviewed in (Kresowik & Griffith, 2009)), however BCG has remained the best option to date for reducing recurrence/progression of NMIBC. Two studies using ives TLR agonists have shown therapeutic potential in the MB49 orthotopic bladder cancer model, the first showing that CpG, a TLR 9 agonist, was superior to BCG therapy (Mangsbo, Nanalga, Essand, Loskog, & Totterman, 2008) and the second showing that R-837 had an antitumor effect in this model (Hayashi et al., 2010). Similarly, Seow et al., have also recently reported anti-tumor effect of ives lactobacillus (Seow et al., 2010).
Numerous attempts to develop compositions comprising attenuated recombinant bacteria and/or attenuated tumor-targeted bacteria, especially attenuated Salmonella typhi, for the inhibition of the growth or reduction of the volume of a solid tumor cancer have been attempted such as, e.g. WO03/063593 (Vion Pharmaceuticals); US2007/0298012 (I. King & L.-M. Zheng); WO2009/098246 (Aeterna Zentaris GmbH); WO2006/076678 (Univ. John Hopkins) and but none of them have achieved sustainable efficacy in human clinical trials (Chorobik, Czaplicki, Ossysek, & Bereta, 2013).
For these reasons, there is still a need to provide a composition that is safer and more efficient than BCG to treat cancer, in particular bladder cancer.